Acanthosis nigricans is a cutaneous manifestation of insulin resistance. This project aims to determine specific mechanisms that cause insulin resistance in the syndrome of acanthosis nigricans which most commonly presents at puberty in females with obesity and oligomenorrhea. In these young adolescents glucose tolerance is often normal in spite of severe insulin resistance. But recent data suggests that progressive loss of compensatory insulin hypersecretion is frequent and there is eventual development of type 2 diabetes mellitus. Other data suggests a markedly increased prevalence of acanthosis nigricans in some ethnic minorities. The long term goals are to (a) fully characterize the nature of the resistance to insulin, (b) delineate the relative importance of genetic and acquired factors in this syndrome, (c) determine the relationship of the ovarian dysfunction and the skin lesions to insulin resistance, and (d)determine what therapy can be effective. The goals are to test the following hypotheses over the next three years. (1) Severe insulin resistance directly affects insulin action in all insulin responsive tissues. Alternatively, this might be limited to insulin responsive glucose uptake in muscle and fat. Stable isotope-labeled glucose and glycerol infusions during euglycemic clamp studies will characterize the dose response curve for insulin-stimulated glucose uptake into muscle, insulin suppression of hepatic glucose output, and insulin suppression of adipocyte glycerol release. (2) The natural course of this insulin resistance syndrome is to lose pancreatic beta cell reserve and eventually develop overt type 2 diabetes. This will be tested by yearly follow-up assessments in all identified patients, consisting of determing glucose tolerance and quantitating insulin secretion and insulin responsiveness. Additional data will be maintained on the course of the obesity, ovaian dysfunction, hypertension, and hyperlipidemia. (3) Parents and siblings will be affected if a specific defect is identified in the proband. Parents and siblings of six severly affected subjects will be evaluated for hyperininsulinemia and in vivo insulin resistance and biochemical characterization will be performed. These proposed experiments may provide important insights into mechanisms of defective insulin action in other common health problems such as obesity and type 2 diabetes mellitus.